An ongoing dialogue on HIV/AIDS, infectious diseases,
February 4th, 2010
Non-Cirrhotic Portal Hypertension: A Rare but Serious Side Effect of ddI
The FDA has issued a warning about an association between use of ddI (didanosine) and the development of non-cirrhotic portal hypertension:
Non-cirrhotic portal hypertension (portal hypertension that is not caused by cirrhosis of the liver) is rare in the United States. It occurs when blood flow in the major vein in the liver (the portal vein) slows down.
–snip–
Because of the potential severity of portal hypertension, including death from hemorrhaging esophageal varices, FDA has revised the Warning and Precautions section of the didanosine drug label to assure safe use of the medication.
Yes, this is a bad one — of the 42 reported cases, 4 patients died; several others required aggressive interventions to reduce the risk of variceal bleeding, including banding/ligation of esophageal varices, transjugular intrahepatic portosystemic shunts (TIPPS), and liver transplantation.
ddI was our second approved antiretroviral, way back in 1991.
Over the years, it has improved — we’ve reduced the dose, now can give it once daily, and have gotten rid of the original bizarre formulation (pictured).
And while it does have reasonable antiviral potency (at least for an NRTI), its myriad potentially severe side effects — neuropathy, pancreatitis, lactic acidosis, to name a few — and the availability of numerous other options mean that there is little reason for a person to be receiving it today.
February 2nd, 2010
Bats in the Bedroom: Canadians Make a Policy Change
ID doctors know all too well the panicky call — usually from a terrified friend, family member, or colleague, or possibly the emergency room or primary care doc — about finding a bat in the house.
Usually in the bedroom.
(In one memorable case, it was the house cat’s leaping in the air to try and catch the bat that woke up the sleeping couple. Each missed pounce led to a loud “thud” as the cat fell to the ground.)
The concern, of course, is bat-related rabies, which I’ve written about before, mostly at the prompting of a fine pair of papers (summarized here and here) published over the past few years by a Canadian group. They have painstakingly documented just how rare human rabies arises from “stealth” bat exposure in the house — 1 case per 2.7 billion person-years
And number of such situations that would need rabies vaccination to prevent one case? From a low of 314,000 to whopping 2.7 million persons.
Well Canada’s National Advisory Committee on Immunization (NACI) has read these papers too, and has decided to stop recommending rabies immunization for bats-in-house-but-no-exposure cases:
Researchers have since reviewed this approach and determined that when there is no obvious contact with a bat, the risk of rabies is extremely rare. Furthermore, there are considerable resource implications to implementing this strategy. Based on the review, which is outlined below, NACI is now recommending intervention only when both of the following conditions apply: 1) There has been direct contact with a bat; and 2) A bite, scratch, or saliva exposure into a wound or mucous membrane cannot be ruled out
According to this nice summary — and hat tip to the author for notifying me of policy change in Canada — it doesn’t sound like the US Advisory Committee on Immunization Practices is ready to make the change quite yet.
But maybe in the next revision of these guidelines?
January 29th, 2010
More on TaqMan Viral Load Testing
Since I first discussed the disruptive effect of introducing Mr. TaqMan to our clinic, many others have weighed in.
One of my favorite reports is a nice paper from the Alabama group, presented first at IDSA, and soon to be published. It shows not only a higher rate of low-level detectable results, but also the increased costs (substantial) due to repeat testing, resistance genotypes sent (and not yielding anything, of course), and the waste of patient and clinic time.
Today, a new complaint: the convoluted word salad that follows the results. To wit, here’s one recent lab report:
HIV-1 PCR: Detected (H)
HIV-1 PCR QUANT: 170 [yes, 6 prior values were undetectable]
HIV-1 PCR QUANT LOG: 2.23
HIV PCR Interpretation: SEE BELOWComments: The quantitative range of this assay is 48-10,000,000 copies/ml (1.7-7.0 log copies/ml). In addition to the sample result being expressed as both copies per milliliter (copies/ml) units and as log(copies/ml), this report interprets if the virus was “Detected”, “Not detected” or “Detected but below Quantitative range” as described below in more detail:
a) “Detected” – means that the viral titer in the sample is above the assay’s lower limit of quantitation (48 copies/ml);
b) “Detected – Not Quant” – means that the viral titer in the sample is below the lower limit of quantitation but above the assay’s lower limit of detection ranging from less than 15 to 46 copies ml across all subtypes of HIV-1 group M;
c) “Not Detected” – means that the viral titer in the sample is below the assay’s lower limit of detection. An interpretation of “Not Detected” does not rule out the presence of HIV-1 that is no detectable for reasons such as PCR inhibitors or HIV-1 virus RNA concentrations below the lower level of detection of the assay.
This test is intended for use in conjunction with clinical presentation and other laboratory indices of disease status as an aid in the clinical management of HIV-1 infected patients. The test can be used to assess patient prognosis by monitoring the effect of antiretroviral therapy on changes in plasma HIV-1 RNA levels during the course of treatment. Limitations: The COBAS AmpliPrep/COBAS TaqMan HIV-1 Test is not intended for use as a screening test for the presence of HIV-1 in blood or blood products or as a diagnostic test to confirm the initial presence of HIV-1infection. General Disclaimer: Interpretation of this test may be affected by the presence of rare viral RNA variants. Methodology: The COBAS AmpliPrep/COBAS TaqMan HIV-1 Test utilizes automated specimen preparation followed by automated reverse transcription, PCR amplification and detection of cleaved dual-labeled detection probes specific to the HIV-1 target RNA. One copy of HIV-1 RNA is equivalent to 1.7 +/- 0.1 International Units (IU) based on the WHO 1st International Standard for HIV-1 RNA for Nucleic Acid-Based Techniques (NAT) (NIBSC 97/656). Test Lab: This assay is approved for In Vitro Diagnostic (IVD) use by the FDA. This test is used for clinical purposes, and it should not be regarded as investigational or for research.
Yikes.
One of my colleagues has responded by going back to sending bDNA. Yes, that test might be less sensitive, but can anyone tell us yet whether these low-level detectable values have any clinical meaning?
January 27th, 2010
No Vicriviroc — Yet
Apparently, Merck — taking over for Schering-Plough — will not seek approval for vicriviroc in treatment-experienced patients:
In two Phase III studies in this patient population, vicriviroc did not meet the primary efficacy endpoint. These studies enrolled a high percentage of patients who had three or more active drugs in their optimized background therapy regimen.
The report goes on to say that the results of these studies will be presented at CROI next month, and that other studies of vicriviroc in treatment-naive patients will continue.
Even though we don’t know the details yet, it’s understandable how this trial didn’t show any benefit for vicriviroc. With the “optimized background therapy” having 3 or more active drugs, how could it? We’re a long way from the TORO/T-20 days, when such “OBT” led to virologic suppression in < 10% of patients.
The control arms in these studies now just do too well. Progress!
Still, given the checkered history of this particular CCR5 antagonist — including a failed phase II study in treatment-naive patients and a possible signal of increased malignancies in another trial — the FDA approval for any indication might be a long hill to climb.
January 17th, 2010
Hey, Didn’t You Used to be the Cause of CFS?
The report last year that xenotropic murine leukemia virus-related virus (XMRV) was found in a high proportion of patients with Chronic Fatigue Syndrome (CFS) caused quite a stir — which is totally understandable given how frustrated the people with CFS are with the lack of adequate explanations for their suffering.
The investigators of the original report even began referring patients to a commercial lab (question #5) to get tested for the virus.
Now some British researchers weigh in. Their findings:
Patients in our CFS cohort had undergone medical screening to exclude detectable organic illness and met the CDC criteria for CFS. DNA extracted from blood samples of 186 CFS patients were screened for XMRV provirus and for the closely related murine leukaemia virus by nested PCR using specific oligonucleotide primers.
(snip)
XMRV or MLV sequences were not amplified from DNA originating from CFS patients in the UK.
Oh darn.
One possible explanation for the negative finding is the differing epidemiology of XMRV in North America and Europe, something also noted in studies of XMRV and prostate cancer.
But the results certainly reinforce what I have suspected for some time, which is that CFS most likely has multiple causes — some infectious, some allergic, some environmental, some emotional, but all yielding a similar clinical phenotype due to underlying genetics and how an individual responds to illness. Yes, XMRV might cause CFS in some people — but seems highly unlikely it does so in all.
I wish it were simpler than that, but alas don’t think it will be.
(Nice summary of the controversy here in ScienceNOW.)
January 14th, 2010
Magic Wand Destroys H1N1 — and More!
From the folks at Hammacher Schlemmer comes this extraordinary device:
Tests performed by an independent antimicrobial testing laboratory showed the wand destroyed 99.98% of the H1N1 virus after a five-second exposure when held 3/4″ above the contaminated surface. Also capable of killing MRSA, mold, and dust mites, the UV-C light penetrates viral and bacterial membranes and destroys their DNA, rendering the microorganisms incapable of reproduction and survival.
It’s worth noting that this thing became available just as the number of flu cases began to plummet.
Do we have this magic wand to thank?
January 10th, 2010
Ceftobiprole’s Long Road to Approval Gets Longer
Cephalosporins with activity against MRSA are out there, but we don’t have them yet. Just recently, the leader of the pack, ceftobiprole, hit another roadblock:
The FDA has indicated in its Complete Response Letter to Johnson & Johnson PRD that it has completed the review of the application and has determined that it cannot approve the application in its present form … The Agency determined that data from Studies BAP00154 and BAP00414 cannot be relied upon because inspections and audits of approximately one-third of the clinical trial sites for these studies found the data from a large proportion of these sites to be unreliable or unverifiable, raising concerns regarding the overall data integrity for both studies
The recommendation from the FDA? Do more studies. (Which means more delay, more $$$.)
One of the great frustrations of antibiotic development is that there’s clearly a need for better drugs for MRSA — unlike, say, a new PPI — yet this pipeline has been pretty dry.
In fact, I bet not a day goes by in medical centers that this need is not readily apparent to ID doctors, surgeons, intensivists, pulmonologists, nephrologists (don’t dialysis patients seem to have the hardest time with MRSA?), endocrinologists (except maybe for people with diabetes), transplant specialists. Pretty much everyone knows this bug is common and hard to treat.
If we start with the premise that vancomycin is the gold standard — and a fairly tarnished one at that — what are our alternatives? Linezolid was a big advance (especially because it can be given orally), but it was approved ten years ago, is bacteriostatic, has certain unavoidable toxicity issues, and is costly, especially compared to other oral antibiotics. Daptomycin was a somewhat smaller step forward, and I confess I still haven’t had the occasion to use telavancin. Trimethoprim-sulfa and tetracyclines are active, but likely less so than vancomycin.
And ceftobiprole? The initial application to the FDA was submitted in 2007; it is already approved in several other countries. And while I have no idea whether the efficacy and safety of the drug will be preferable to what we have now — perhaps someone from Canada or Hong Kong or Europe can clue me in — just having more options for MRSA seems like a very good thing.
Ceftaroline/NXL104, anyone?
January 1st, 2010
Top 10 Stories of the Year
No end-of-year wrap-up is complete without a “Top 10” list, and Journal Watch: AIDS Clinical Care is no exception.
This year we did two lists, one chosen by the Editors, the other a numeric tally of what’s read on line by the Readers.
The “When to start” issue was the top story from the Editors.
The big hit from Readers was the case of occupational exposure from a source patient who refused testing. (I posted it here this past June.)
Not much overlap between the two lists, reflecting I think several issues:
- Editors are choosing from scientific advances; the readers from what they find clinically useful or interesting. They can be the same thing, but they don’t have to be. (Hardly doubt many were counting on IL-2 to enter the clinics this year, for example.)
- What people read on-line may be different from what they consider important. Some on-line stuff is just fun. Or funny. Or controversial.
- The on-line readership is given a big boost from Physician’s First Watch.
Hope you enjoy, and Happy New Year!
December 28th, 2009
Holiday Surprise: Generic Valacyclovir
Last week one of my patients went to refill a Valtrex prescription, and was offered generic valacyclovir for the first time. It made him nervous, so he requested I write a “brand-name only” script.
I confess the existence of a generic formulation of valacyclovir — which according to the PharmD here has been available for several months — was news to me. 
(Generic acylcovir and famciclovir* have been available for years.)
And while there is no reason to suspect generic valacylcovir will have any unusual issues related to efficacy or toxicity compared to the branded version, this Times article reminds us that this is not always the case:
Joe Graedon, who has been writing about pharmaceuticals for three decades and runs a consumer advocacy Web site, the People’s Pharmacy (peoplespharmacy.com), was 100 percent behind generics for many years. “We were the country’s leading generic enthusiasts,” he told me recently. But over the last eight or nine years, Mr. Graedon began hearing about “misadventures” from people who read his syndicated newspaper column.
What follows are some anecdotal experiences and opinions — largely from the psych, neurology, and cardiology fields — about the potential dangers of even slight differences in bioequivalence or excipients between branded and generic drugs. For even more of the same, read the comments section here.
Which brings me back to my patient: Since he’s taking the Valtrex for an unusual reason (recurrent HSV-related meningitis), and since he’s willing to pay extra for the branded version, I went ahead and wrote the “brand name only” script.
My thinking? Let’s see what a year or so of experience with generic valacyclovir brings us when used for more typical indications before making the switch.
(*Why isn’t this spelled “famcyclovir”?)
December 20th, 2009
Infections from Transplant Donors: Rare but Inevitable
Two kidney transplant patients are critically ill due to Balamuthia mandrillaris encephalitis they acquired from the organ donor:
The same infection probably killed the organ donor, but it was not diagnosed; his doctors thought he had an autoimmune disease. Two other patients also received heart and liver transplants from the donor, but neither has become ill.
Infections due to free-living amoeba are extremely rare; those acquired from transplant even more so.
Hence the lesson from these transplant-related cases is not that there’s a new threat to the health of transplant recipients.
But it’s a reminder that the infection risk will never be zero. We cannot test donors for every possible disease, and the shortage of available organs means that some donor-derived infections will inevitably continue.
(These LCMV cases caused quite the stir around here a few years ago.)
Organ transplantation remains one of the great miracles of medicine. With the caveat that I don’t know further details about this donor’s case, it seems that a (small) risk of donor-derived infection is the price of doing business.
(Edit: And now the WSJ has weighed in here. Focus is on those harmed by the infection, understandably, and the need to make the process safer — but the fact remains that transplant will never be 100% safe.)
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
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